1. Field of the Invention
The present invention is directed to novel steroid derivatives of the androstane and pregnane series, as well as pharmaceutical compositions and methods for modulating brain excitability. More particularly, the invention relates to 3xcex1-hydroxy, 17-(un)substituted derivatives of the androstane series and 21-substituted derivatives of the pregnane series.
2. Related Art
Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately xe2x88x9280 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K+, Naxe2x88x92, Clxe2x88x92, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from xe2x88x9280 mV to xe2x88x9250 mV). This effect is mediated by postsynaptic nicotinic receptors which are stimulated by acetylcholine to increase membrane permeability to Na+ ions. The reduced membrane potential stimulates neuronal excitability in the form of a postsynaptic action potential.
In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by GABA, a neurotransmitter. GABA has a profound influence on overall brain excitability because up to 40% of the neurons in the brain utilize GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC to facilitate the flow of chloride ions down an electrochemical gradient of the GRC into the cell. An intracellular increase in the levels of this anion causes hyperpolarization of the transmembrane potential, rendering the neuron less susceptible to excitatory inputs (i.e., reduced neuron excitability). In other words, the higher the chloride ion concentration in the neuron, the lower the brain excitability (the level of arousal).
It is well-documented that the GRC is responsible for the mediation of anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA or facilitate the effects of GABA (e.g., the therapeutically useful barbiturates and benzodiazepines (BZs), such as Valium) produce their therapeutically useful effects by interacting with specific regulatory sites on the GRC.
Accumulated evidence has now indicated that in addition to the benzodiazepine and barbiturate binding site, the GRC contains a distinct site for neuroactive steroids (Lan, N. C. et at, Neurochem. Res. 16:347-356 (1991)). Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3xcex1-hydroxy-5-reduced pregnan-20-one and 3xcex1,21-dihydroxy-5-reduced pregnan-20-one, metabolites of hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M. D. et al., Science 232:1004-1007 (1986); Harrison, N. L. et al., J. Pharmacol. Exp. Ther. 241:346-353 (1987)). However, the therapeutic usefulness of these steroid metabolites and their derivatives (neuroactive steroids) was not recognized by workers in the field due to an incomplete understanding of the potency and site of action of these neuroactive steroids. Applicants"" invention relates in part to a pharmaceutical application of the knowledge gained from a more developed understanding of the potency and site of action of certain steroid compounds.
The ovarian hormone progesterone and its metabolites have been demonstrated to have profound effects on brain excitability (Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130:19-24 (1985); Pfaff, D. W. and McEwen, B. S., Science 219:808-814 (1983); Gyermek et al., J. Med. Chem. 11:117 (1968); Lambert, J. et al., Trends Pharmacol. Sci. 8:224-227 (1987)). The levels of progesterone and its metabolites vary with the phases of the menstrual cycle. It has been well documented that progesterone and its metabolites decrease prior to the onset of menses. The monthly recurrence of certain physical symptoms prior to the onset of menses has also been well documented. These symptoms, which have become associated with premenstrual syndrome (PMS) include stress, anxiety, and migraine headaches (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). Patients with PMS have a monthly recurrence of symptoms that are present in premenses and absent in postmenses.
In a similar fashion, a reduction in progesterone has also been temporally correlated with an increase in seizure frequency in female epileptics, i.e., catamenial epilepsy (Ladlaw, J., Lancet, 1235-1237 (1956)). A more direct correlation has been observed with a reduction in progesterone metabolites (Rosciszewska et al., J. Neurol. Neurosurg. Psych. 49:47-51 (1986)). In addition, for patients with primary generalized petit mal epilepsy, the temporal incidence of seizures has been correlated with the incidence of the symptoms of premenstrual syndrome (Backstrom, T. et al., J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983)). The steroid deoxycorticosterone has been found to be effective in treating patients with epileptic spells correlated with their menstrual cycles (Aird, R. B. and Gordan, G., J. Amer. Med. Soc. 145:715-719 (1951)).
A syndrome also related to low progesterone levels is postnatal depression (PND). Immediately after birth, progesterone levels decrease dramatically leading to the onset of PND. The symptoms of PND range from mild depression to psychosis requiring hospitalization. PND is also associated with severe anxiety and irritability. PND-associated depression is not amenable to treatment by classic antidepressants and women experiencing PND show an increased incidence of PMS (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)).
Collectively, these observations imply a crucial role for progesterone and deoxycorticosterone and more specifically their metabolites in the homeostatic regulation of brain excitability, which is manifested as an increase in seizure activity or symptoms associated with catamenial epilepsy, PMS and PND. The correlation between reduced levels of progesterone and the symptoms associated with PMS, PND, and catamenial epilepsy (Backstrom, T. et al., J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983)); Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)) has prompted the use of progesterone in their treatment (Mattson et al., xe2x80x9cMedroxyprogesterone therapy of catamenial epilepsy,xe2x80x9d in Advances in epileptology: XVth Epilepsy International Symposium, Raven Press, New York (1984), pp. 279-282, and Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone is not consistently effective in the treatment of the aforementioned syndromes. For example, no dose-response relationship exists for progesterone in the treatment of PMS (Maddocks, et al., Obstet. Gynecol. 154:573-581 (1986); Dennerstein, et al., Brit. Med. J. 290:16-17 (1986)).
Templeton et al., Steroids 48:339-346 (1986) discloses a stereoselective and regioselective reduction of steroid ketones to form axial alcohols at C-3. The compound 17xcex2-methoxy-2xcex2-methyl-5xcex1-androstan-3xcex1-ol is formed from 17xcex2-methoxy-2xcex1,3xcex1-epoxy-5xcex1-androstane.
Grieco et al., J. Am. Chem. Soc. 11:7799-7801 (1990) discloses the use of 17xcex2-methoxy-5xcex1-androstan-3xcex1-ol as a starting material for forming conjugates comprising metalloporphyrins attached to steroid substrates.
Babcock et al., U.S. Pat. No. 4,297,350, issued Oct. 27, 1991, broadly discloses steroidal androstane and androstane 17-ethers and their use as male contraceptives.
Neef et al., Tetrahedron Letters 21:903-906 (1980) discloses the compound 17xcex2-methoxymethoxy-3xcex2-(1-propynyl)-5xcex1-androsten-3xcex1-ol as an intermediate in the formation of steroid derivatives.
FR 1,437,361, published May 6, 1966 and U.S. Pat. No. 3,135,744, issued Jun. 2, 1964, disclose the 17-(2-methyl-2-butenyl) and cycloalkenyl ethers of 5xcex1-androstane-3xcex1,17xcex2-diol and 3-lower alkanoyl esters thereof. The compounds are taught to have androgenic and/or anabolic activity.
Phillips et al, U.S. Pat. No. 4,197,296, issued Apr. 8, 1980, discloses steroids of the androstane series which possess a 3xcex1-hydroxy group, a 5xcex1- or 5xcex2-hydrogen atom, and an 11xcex1-substituted amino group wherein the 17 position may be unsubstituted. The compound 11xcex1-N,N-dimethylamino-2xcex2-ethoxy-5xcex1-androstan-3xcex1-ol is disclosed. The patent discloses that these compounds have anesthetic activity.
Phillips et al., U.S. Pat. No. 3,882,151, issued May 6, 1975, and Phillips et al., U.S. Pat. No. 3,969,345, issued Jul. 13, 1976, disclose 3xcex1-oxygenated pregnane 21-ethers possessing a 3xcex1-hydroxy group or an ester thereof, a keto group in the 20-position, and an etherified hydroxyl group in the 21-position. The 21-ether substituent is preferably an alkoxy, cycloalkoxy, aralkoxy, or aryloxy group that may carry additional substituents. The patents disclose that these compounds have anesthetic activity.
Phillips et al., U.S. Pat. No. 3,959,260, issued May 25, 1976, discloses steroid anesthetics of the pregnane and 19-norpregnane series which possess a 3xcex1-hydroxy group, a 20-oxo group, and at the 21-position the residue of a sulfur containing nucleophile or a sulphone or sulfoxide grouping. The 3xcex2-substituent may be either hydrogen or alkyl.
Clayton et al., U.S. Pat. No. 3,822,298, issued Jul. 2, 1974, discloses a process for preparing 3xcex1-hydroxy-5xcex1-steroids. The patent discloses the preparation of 21-benzyloxy-3xcex1-hydroxy-5xcex1-pregnane-11,20-dione.
The present invention is directed to novel steroid derivatives of the androstane and pregnane series, as well as pharmaceutical compositions and methods for modulating brain excitability. More particularly, the invention relates to 3xcex1-hydroxy, 17-(un)substituted derivatives of the androstane series and 21-substituted derivatives of the pregnane series. These derivatives are capable of acting at a recently identified site on the GRC, thereby modulating brain excitability in a manner that alleviates stress, anxiety, insomnia, mood disorders that are amenable to GRC-active agents (such as depression) and seizure activity.
The steroid derivatives of this invention are those having the general structural formula (I): 
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are further defined herein and the dotted lines are single or double bonds. The structure having Formula I includes androstanes, pregnanes (R4=methyl), 19-norandrostanes, and norpregnanes (R4=H).
The present invention also includes pharmaceutically acceptable esters and salts of the compounds of Formula I, including acid addition salts. It is believed that the 3xcex1-hydroxyl may also be masked as a pharmaceutically acceptable ester due to the fact that the ester will be cleaved off as the prodrug is converted to drug form. These are referred to herein as cleavable esters.
The compounds of the present invention are modulators of the excitability of the central nervous system as mediated by their ability to regulate chloride ion channels associated with the GABA receptor complex. Applicants"" experiments have established that these compounds have anticonvulsant, anxiolytic, and sedative hypnotic activity similar to the actions of known agents such as the BZs, but act at a distinct site on the GRC.
The relationship of endogenous metabolites of progesterone to processes associated with reproduction (estrus cycle and pregnancy) is well established (Marker, R. E. et al., J. Am. Chem. Soc. 59:616-618 (1937)). However, it was just recently recognized how to treat disorders by modulating brain excitability through the use of steroid metabolites and their derivatives. See, U.S. Pat. No. 5,208,227, issued May 4, 1993; U.S. Pat. No. 5,120,723, issued Jun. 9, 1992; and U.S. Pat. No. 5,232,917, issued Aug. 3, 1993.
Desirable objects of the pharmaceutical compositions and methods of this invention are the treatment of stress, anxiety, PMS, PND, and seizures such as those caused by epilepsy to ameliorate or prevent the attacks of anxiety, muscle tension, and depression common with patients suffering from these central nervous system abnormalities. An additional desirable object of the compositions and methods is to treat insomnia and produce hypnotic activity. Another desirable object of the compounds and methods is to induce anesthesia, particularly by intravenous administration. The present invention is directed to novel compounds and their use in pharmaceutical compositions and methods to treat such disorders by modulating brain excitability.
Another aspect of the present invention relates to a method of inducing sleep and maintaining substantially the level of REM sleep that is found in normal sleep, wherein substantial rebound insomnia, as defined herein, is not induced. This method comprises administering an effective amount of a compound of the invention. The compounds of the invention are able to increase NREM sleep and the total sleep period, without substantially affecting the amount of REM sleep.